In addition to synthesizing new glucose, hepatic gluconeogenesis disposes of a large daily load of lactic acid. Studies in this and other laboratories have implicated failure of hepatic lactic acid disposal as a major pathophysiologic factor in experimental models of lactic acidosis. Recent studies in this laboratory demonstrate that a fall in the intracellular pH of liver, produced by a variety of methods, is associated with and may be responsible for the failure of the liver to extract lactate. There have been a number of suggestions as to the mechanism of this effect but no clear explanation has been established. The studies outlined in this proposal are designed to examine the relationship between liver intracellular pH (pHi) and gluconeogenesis. In addition, we will examine the effects of several factors known to modulate gluconeogenesis on the pHi-gluconeogenesis relationship. The studies will be carried out in a model system-hepatocyte monolayer culture. We have developed a method for measurement of pHi in this culture system and will apply this method to the studies outlined. Results of these studies will provide information as to the regulatory role of intracellular pH in gluconeogenesis and will suggest avenues for further investigation.